Restoring Balance: Biologics in Immune-Disorder Research

Autoimmune diseases arise when the immune system recognizes a normal part of the body as foreign and assumes a hostile stance towards it. Treatment has proven difficult, given the complexity of the immune system, with global immunosuppressants commonly used to control disease severity over prolonged time periods.1 Biologics have revolutionized autoimmune disease therapeutic research. Their ability to target specific immune cells or immunomodulatory molecules allows scientists to target individual, potentially pathogenic mechanisms rather than resort to global immunosuppression. The promise of biologics has led to significant research efforts regarding not only their potential therapeutic usage, but also their suitability in the laboratory for uncovering the underlying mechanisms of chronic conditions such as arthritis and inflammatory bowel diseases.2

Biological agents in arthritis research and therapeutics

Rheumatoid arthritis (RA) is a chronic autoimmune disease that predominantly affects the synovial joints, potentially resulting in range-of-motion loss and decline in quality of life. Many cells (e.g., endothelial cells, macrophages, T and B cells) and other factors (including cytokines, chemokines, angiogenesis, and reactive oxygen species) have been implicated in the pathogenesis and progression of RA.3 

From a therapeutic standpoint, biologic agents are generally developed and used to target either cell-driven or cytokine-driven mechanisms. Here, antibodies are overwhelmingly the agent of choice, with multiple antibodies targeting cytokines such as TNFα, IL-6, IL-1, and IL-17 already FDA approved or undergoing clinical trials. Antibodies have also been used to target immune cells, seeking to impede or dampen their function. Currently available B-cell targeting agents selectively induce subpopulation depletion through cytotoxicity, apoptosis, or cell cycle suspension, while T-cell targeting agents prevent T cell activation by antagonizing the CTLA4-CD80/86 interaction.3,4 The development of agents that antagonize pro-RA cellular signaling pathways (e.g., JAK-STAT) have also been investigated.

Biological agents in inflammatory bowel disease research and therapeutics

Inflammatory bowel diseases (IBDs) are a group of chronic autoimmune disorders featuring pathological inflammation of the intestinal tract. The most well-known of these include Crohn’s disease (CD) and ulcerative colitis (UC). While IBDs differ in terms of affected regions, they are generally characterized by pronounced mucosal inflammation and morphological degradation.5 Both steroidal and nonsteroidal anti-inflammatory agents are commonly used to treat IBD, with surgical intervention necessary for severe cases.5 

The elevated production of pro-inflammatory cytokines is a hallmark of both UC and CD. As such, researchers are investigating the potential of cytokine-targeting antibodies for reducing disease severity and inducing clinical remission.5,6 TNFα is the most well investigated, with several anti-TNFα antibodies currently in clinical use for both diseases.6,7 Other potential antibody targets for CD include IL-12/IL-23 and integrins, while the effects of antibody-based adhesion molecules and JAK signaling inhibition on UC are being studied.6,7

One step at a time: biologics have changed autoimmune disease research

Autoimmune diseases have long been a perplexing problem for researchers and clinicians alike. The advent of biologics has allowed therapeutic research to move away from global immunosuppressants and to investigate the suitability of selective anti-inflammatory agents. Having the ability to target specific elements and hallmarks of autoimmune disease will also aid researchers in isolating variables for in-depth study, allowing more insights to be gained regarding the pathophysiological mechanisms for these complex disorders.

References
  1. M.D. Rosenblum et al., “Treating human autoimmunity: current practice and future prospects,” Sci Transl Med, 4(125):125sr1, 2012.
  2. M. Her and A. Kavanaugh, “Alterations in immune function with biologic therapies for autoimmune disease,” J Allergy Clin Immunol, 137(1):19-27, 2016.
  3. Q. Guo et al., “Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies,” Bone Res, 6:15, 2018. 
  4. P.M. Brown and J.D. Isaacs, “Rheumatoid arthritis: an evolutionary force in biologics,” Curr Pharm Des, 21(17):2170-2178, 2015.
  5. B.A. Hendrickson et al., “Clinical aspects and pathophysiology of inflammatory bowel disease,” Clin Microbiol Rev, 15(1):79-94, 2002.
  6. J. Côté-Daigneault et al., “Biologics in inflammatory bowel disease: what are the data?” United European Gastroenterol J, 3(5): 419-428, 2015.
  7. S.C. Park and Y.T. Jeen, “Current and emerging biologics for ulcerative colitis,” Gut Liver, 9(1): 18-27, 2015.
 
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